Haematologic malignancies commonly arise from the bone marrow lesion, yet there are currently no effective targeted therapies against tumour cells in this location. Here we constructed a bone-marrow-targeting nanosystem, CSF@E-Hn, which is based on haematopoietic-stem-cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of haematologic malignancies. CSF@E-Hn targets the bone marrow and, thanks to the gripper ligands, pulls together tumour cells and natural killer cells, activating the latter for specific tumour cell targeting and elimination. The therapeutic efficacy was validated in mice bearing acute myeloid leukaemia and multiple myeloma. The comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone-marrow-targeted nanosystem promoted haematopoietic stem cell differentiation, boosted memory T cell generation and maintained bone homoeostasis, with long-term prevention of relapse. Our nanosystem represents a promising strategy for the treatment of haematologic malignancies.

血液系统恶性肿瘤通常由骨髓病变引起，但目前尚无针对该部位肿瘤细胞的有效靶向治疗方法。在这里，我们构建了一种骨髓靶向纳米系统 CSF@E-Hn，它基于造血干细胞衍生的纳米囊泡，装饰有抓手配体（aPD-L1 和 aNKG2D）并封装有集落刺激因子（CSF）用于治疗血液系统恶性肿瘤。 CSF@E-Hn 以骨髓为目标，借助抓手配体，将肿瘤细胞和自然杀伤细胞聚集在一起，激活后者以实现特定的肿瘤细胞靶向和消除。该治疗效果在患有急性髓性白血病和多发性骨髓瘤的小鼠中得到验证。对治疗后骨髓微环境的综合评估表明，脑脊液整合到骨髓靶向纳米系统中可以促进造血干细胞分化，促进记忆T细胞生成并维持骨稳态，从而长期预防复发。我们的纳米系统代表了治疗血液恶性肿瘤的一种有前途的策略。